chr2-21044222-G-A

Variant names:

• chr2-21044222-G-A
• rs9282608
• ENST00000762414.1:n.68G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000762414.1(ENSG00000299295):​n.68G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 269,094 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (150 hom., cov: 32)
  • Exomes 𝑓: 0.012 (40 hom.)
• Consequence: ENSG00000299295 ENST00000762414.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.187
• Publications: 2 publications found

Genes affected

ENSG00000299295 (HGNC:):

APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]

APOB Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, type B

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• familial hypobetalipoproteinemia 1

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-21044222-G-A is Benign according to our data. Variant chr2-21044222-G-A is described in ClinVar as Benign. ClinVar VariationId is 3250494.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.-277C>T		upstream_gene_variant		ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.-277C>T		upstream_gene_variant		1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4017 AN: 152210 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.0710

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.0811

Gnomad SAS AF: 0.00723

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.0201

GnomAD4 exome AF: 0.0119 AC: 1392 AN: 116764 Hom.: 40 AF XY: 0.0111 AC XY: 676 AN XY: 60780

African (AFR) AF: 0.0669 AC: 212 AN: 3170

American (AMR) AF: 0.0241 AC: 77 AN: 3196

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 54 AN: 4120

East Asian (EAS) AF: 0.0822 AC: 831 AN: 10114

South Asian (SAS) AF: 0.00278 AC: 3 AN: 1078

European-Finnish (FIN) AF: 0.00218 AC: 24 AN: 11028

Middle Eastern (MID) AF: 0.00482 AC: 3 AN: 622

European-Non Finnish (NFE) AF: 0.00122 AC: 93 AN: 75950

Other (OTH) AF: 0.0127 AC: 95 AN: 7486

GnomAD4 genome AF: 0.0266 AC: 4052 AN: 152330 Hom.: 150 Cov.: 32 AF XY: 0.0263 AC XY: 1958 AN XY: 74502

African (AFR) AF: 0.0715 AC: 2973 AN: 41588

American (AMR) AF: 0.0254 AC: 389 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.0813 AC: 419 AN: 5154

South Asian (SAS) AF: 0.00724 AC: 35 AN: 4834

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00148 AC: 101 AN: 68024

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0157 Hom.: 8

Bravo AF: 0.0328

Asia WGS AF: 0.0460 AC: 162 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypercholesterolemia Benign:1

Jun 23, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		0.19
PromoterAI		-0.030	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9282608; hg19: chr2-21267094;